A Novel RING Finger Protein Implicated in Neoplasia

描述（由申请人提供）：杂合性缺失（洛）和 1号染色体短臂上的细胞遗传学畸变已经在 组织学上多种多样的人类癌症。至少有三个独立的区域， 染色体1 p被认为是肿瘤抑制基因的位点 与神经母细胞瘤的发生和/或进展相关， 和结肠癌。我们已经确定了一个基因，CAR-1（癌症相关 RING-1），它精确地映射到1号染色体上的这些区域之一。我们 假设该基因是1号染色体上的肿瘤抑制基因之一 P，并且其破坏导致肿瘤发生。具体目标是 研究建议是：1）获得研究CAR-1所需的工具， 包括全长cDNA序列和抗体，2）筛选突变 在原发性肿瘤样品以及癌细胞系中的CAR-1中，3）确定 CAR-1在体外和体内生长调节中的作用，并分析了CAR-1在体外和体内生长调节中的作用。 基因的特定蛋白质结构域在突变的生长调节中的作用 分析，以及4）阐明CAR-1基因的细胞靶标或辅因子 通过蛋白质-蛋白质相互作用研究产品。因为CAR-1共享 有趣的结构基序与一类重要的基因，其中许多 在肿瘤发生中起作用，如本文所述， 建议将有助于更好地了解7 b5和其他 与癌症进展相关的基因。

DESCRIPTION (provided by applicant): Loss of heterozygosity (LOH) and cytogenetic aberrations on the short arm of chromosome 1 have been observed in histologically diverse human cancers. At least three separate regions on chromosome 1p have been implicated as sites for tumor suppressor genes associated with the initiation and/or progression of neuroblastoma, and breast and colon carcinoma. We have identified a gene, CAR-1 (Cancer Associated RING-1), that maps exactly into one of these regions on chromosome 1. We hypothesize that this gene is one of the tumor suppressor genes on chromosome 1 p and that its disruption results in tumorigenesis. The specific aims of this research proposal are to: 1) Obtain the tools necessary to study CAR-1, including the full-length cDNA sequence and antibodies, 2) Screen for mutations in CAR-1 in primary tumor samples as well as cancer cell lines, 3) Determine the role of CAR-1 in in vitro and in vivo growth regulation and dissect the roles of the gene's specific protein domains in growth regulation by mutational analysis, and 4) Elucidate cellular targets or co-factors of the CAR-1 gene product by protein-protein interaction studies. Because CAR-1 shares interesting structural motifs with an important class of genes, many of which play roles in oncogenesis, molecular analysis of the gene as described in this proposal will lead to a better understanding of the functions of 7b5 and other related genes associated with cancer progression.